Arp Gabriela, Jiang Angela, Dufault-Thompson Keith, Levy Sophia, Zhong Aoshu, Wassan Jyotsna Talreja, Grant Maggie, Li Yue, Hall Brantley, Jiang Xiaofang
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, College Park, Maryland, USA.
National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA.
bioRxiv. 2024 Oct 5:2024.10.04.616736. doi: 10.1101/2024.10.04.616736.
The metabolism of steroids by the gut microbiome affects hormone homeostasis, impacting host development, mental health, and reproductive functions. In this study, we identify the Δ-3-ketosteroid 5β-reductase, 3β-hydroxysteroid dehydrogenase/Δ isomerase, and Δ-3-ketosteroid reductase enzyme families encoded by common human gut bacteria. Through phylogenetic reconstruction and mutagenesis, We show that 5β-reductase and Δ-3-ketosteroid reductase have evolved to specialize in converting diverse 3-keto steroid hormones into their 5β- and Δ-reduced derivatives. We also find that the novel 3β-hydroxysteroid dehydrogenase/Δ isomerase is fused with 5β-reductase in multiple species, streamlining the multi-step conversion of pregnenolone, a steroid hormone precursor, into epipregnanolone. Through metagenomic analysis, we reveal that these enzymes are prevalent in healthy populations, being enriched in females over males. These findings provide the molecular basis for studying microbial steroid metabolism in the gut, offering insights into its potential impact on hormonal health in hosts, especially in the context of women's health.
肠道微生物群对类固醇的代谢会影响激素稳态，进而影响宿主的发育、心理健康和生殖功能。在本研究中，我们鉴定了常见人类肠道细菌编码的Δ-3-酮类固醇5β-还原酶、3β-羟基类固醇脱氢酶/Δ异构酶和Δ-3-酮类固醇还原酶酶家族。通过系统发育重建和诱变，我们表明5β-还原酶和Δ-3-酮类固醇还原酶已经进化，专门将多种3-酮类固醇激素转化为其5β-和Δ-还原衍生物。我们还发现，新型3β-羟基类固醇脱氢酶/Δ异构酶在多个物种中与5β-还原酶融合，简化了类固醇激素前体孕烯醇酮向表孕烷醇酮的多步转化。通过宏基因组分析，我们发现这些酶在健康人群中普遍存在，在女性中比男性中更丰富。这些发现为研究肠道微生物类固醇代谢提供了分子基础，有助于深入了解其对宿主激素健康的潜在影响，尤其是在女性健康方面。
